The objective of this proposal is to determine, in a double-blinded prospective trial, whether the short and long term outcome in patients with Lyme disease and erythema migrans can be altered by varying the duration of standard oral antimicrobial therapy, or by supplementing oral therapy with one 2 gram dose of intravenous ceftriaxone given at the beginning of treatment. In addition, by prospectively studying such patients over 30 months via neuro-psychiatric testing, audiometry, and careful physical examination, we hope to determine the true incidence of rheumatologic and neuro-psychiatric complications of treated Lyme disease, better define the "post-Lyme syndrome," and determine the risk factors (e.g. complicated vs. uncomplicated EM, multiple EM lesions, history of psychiatric illness) for these entities. Much of what we know about Lyme disease is based upon non-randomized and/or non-blinded therapeutic trials with relatively few patients and brief periods of follow-up. In particular, new trials are needed that are prospective and double-blinded, and compare different durations of anti-microbial therapy. We will enroll 150 patients over 2 years, and randomize them to receive either 1) one 2 gr IV dose of ceftriaxone plus doxycycline 100 mg po BID x 10 days, 2) doxycycline 100 mg po BID x 20 days, plus placebo IV treatment, or 3) doxycycline 100 mg po BID x 10 days, plus placebo IV treatment. By following these patients over 30 months we hope to define better the sequelae of Lyme disease, their risk factors, and patient response to therapy. Our center, experienced in enrolling patients for prospective trials in EM, and located in a county with one of the highest incidences of Lyme disease in the United States (1), is uniquely situated to accomplish these goals.